Oct-3/4 maintains the proliferative embryonic stem cell state via specific binding to a variant octamer sequence in the regulatory region of the UTF1 locus
Oct-3/4 maintains the proliferative embryonic stem cell state via specific binding to a variant octamer sequence in the regulatory region of the UTF1 locus
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DOI：
10.1128/mcb.25.12.5084-5094.2005
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发表时间：
2005-06-01
影响因子：
5.3
通讯作者：
Okuda, A
中科院分区：
文献类型：
--
作者：
Nishimoto, M;Miyagi, S;Okuda, A
POU转录因子Oct-3/4已被证明是维持胚胎干细胞（ES）特性的关键。然而，其功能背后的分子机制仍然难以捉摸。我们以前已经表明，在POU转录因子家族的蛋白质，Oct-3/4单独能够结合到UTF 1基因的调控区，该基因与Sox-2一起具有变体八聚体序列。在这里，我们使用Oct-3/4-Oct-6嵌合体证明，蛋白质在UTF 1增强子上与Sox-2形成复合物的能力与在ES细胞中维持干细胞状态的能力之间存在精确的相关性。不同的嵌合蛋白显示出在UTF 1调控区上形成含Sox-2的复合物的不同能力，复合物形成的效率降低，伴随着UTF 1表达水平和细胞增殖速率的降低。在这些生长缓慢的细胞中过表达UTF 1能够将其增殖率恢复到野生型水平。此外，还观察到UTF 1对畸胎瘤形成有影响。这些结果表明Oct-3/4通过UTF 1基因的激活诱导ES细胞的快速增殖和致瘤特性的分子途径。
The POU transcription factor Oct-3/4 has been shown to be critical for maintaining embryonic stem (ES) cell character. However, the molecular mechanisms underlying its function remain elusive. We have previously shown that among the POU transcription factor family of proteins, Oct-3/4 alone is able to bind to the regulatory region of the UTF1 gene bearing a variant octamer sequence together with Sox-2. Here, we demonstrate using Oct-3/4-Oct-6 chimeras that there is a precise correlation between the ability of proteins to form a complex on the UTF1 enhancer with Sox-2 and the ability to maintain the stem cell state in ES cells. Different chimeric proteins show differential abilities to form a Sox-2-containing complex on the UTF1 regulatory region, with a decrease in efficiency of the complex formation accompanied by a decrease in the level of UTF1 expression and the rate of cell proliferation. Overexpression of UTF1 in these slow-growing cells was able to restore their proliferation rate to wild-type levels. Moreover, UTF1 was also observed to have an effect on teratoma formation. These results suggest a molecular pathway by which Oct-3/4 induces rapid proliferation and tumorigenic properties of ES cells through activation of the UTF1 gene.